UCL Institute of Ophthalmology, University College London, London, United Kingdom; Moorfields Eye Hospital, London, United Kingdom.
Genetics Research Centre, Molecular and Clinical Sciences, St George's University of London, London, United Kingdom.
Am J Ophthalmol. 2019 Nov;207:87-98. doi: 10.1016/j.ajo.2019.05.001. Epub 2019 May 8.
Familial exudative vitreoretinopathy (FEVR) is a rare finding in patients with genetic forms of microcephaly. This study documents the detailed phenotype and expands the range of genetic heterogeneity.
Retrospective case series.
Twelve patients (10 families) with a diagnosis of FEVR and microcephaly were ascertained from pediatric genetic eye clinics and underwent full clinical assessment including retinal imaging. Molecular investigations included candidate gene Sanger sequencing, whole-exome sequencing (WES), and whole-genome sequencing (WGS).
All patients had reduced vision and nystagmus. Six were legally blind. Two probands carried bi-allelic LRP5 variants, both presenting with bilateral retinal folds. A novel homozygous splice variant, and 2 missense variants were identified. Subsequent bone density measurement identified osteoporosis in one proband. Four families had heterozygous KIF11 variants. Two probands had a retinal fold in one eye and chorioretinal atrophy in the other; the other 2 had bilateral retinal folds. Four heterozygous variants were found, including 2 large deletions not identified on Sanger sequencing or WES. Finally, a family of 2 children with learning difficulties, abnormal peripheral retinal vasculogenesis, and rod-cone dystrophy were investigated. They were found to have bi-allelic splicing variants in TUBGCP6. Three families remain unsolved following WES and WGS.
Molecular diagnosis has been achieved in 7 of 10 families investigated, including a previously unrecognized association with LRP5. WGS enabled molecular diagnosis in 3 families after prior negative Sanger sequencing of the causative gene. This has enabled patient-specific care with targeted investigations and accurate family counseling.
家族性渗出性玻璃体视网膜病变（FEVR）在遗传性小头畸形患者中较为罕见。本研究记录了详细的表型，并扩展了遗传异质性的范围。
回顾性病例系列。
从儿科遗传眼病诊所确定了 12 名（10 个家系）FEVR 和小头畸形患者，并进行了全面的临床评估，包括视网膜成像。分子研究包括候选基因 Sanger 测序、外显子组测序（WES）和全基因组测序（WGS）。
所有患者均有视力下降和眼球震颤。6 名患者视力严重受损。2 名先证者携带 LRP5 双等位基因突变，均表现为双侧视网膜皱褶。发现了一种新的纯合剪接变异体和 2 种错义变异体。随后的骨密度测量发现 1 名先证者患有骨质疏松症。4 个家系存在 KIF11 杂合变异体。2 名先证者一眼有视网膜皱褶，另一眼有脉络膜视网膜萎缩；另外 2 名先证者有双侧视网膜皱褶。发现了 4 种杂合变异体，包括 2 种未在 Sanger 测序或 WES 上发现的大片段缺失。最后，一个有 2 名学习困难儿童的家系，其周边视网膜血管生成异常和 rods-cone 营养不良，经调查发现 TUBGCP6 存在双等位基因剪接变异体。WES 和 WGS 后，仍有 3 个家系未解决。
在所研究的 10 个家系中，有 7 个家系实现了分子诊断，包括之前未被识别的与 LRP5 的关联。WGS 使 3 个先前在致病基因上进行了阴性 Sanger 测序的家系能够进行分子诊断。这使患者能够获得个体化的治疗，并进行有针对性的检查和准确的家庭咨询。
